This invention relates to a cell-free process for producing a cephalosporin antibiotic.
Cephalosporins comprise a group of .beta. lactam penicillin-like antibiotic substances which are soluble in water and exhibit activity against certain penicillin resistant staphylococci. Examples of cephalosporin antibiotics include desacetylcephalosporin C, deacetoxycephalosporin C, 7 methoxy cephalosporin C, cephamycin A and B, and cephalosporin C. The latter has the structural formula: ##STR1## Penicillin N, an example of a related family of antibiotics, has the structure set forth below: ##STR2##
A review of the structural formulae of the above noted .beta. lactam compounds indicates that it would be theoretically possible to convert penicillins such as penicillin N to cephalosporins if the five membered thiazolidine ring of the penicillins could be expanded to the six membered dihydrothiazine ring characteristic of the cephalosporins. Indeed, in the Journal of American Chemical Society, Vol. 85, at pages 1896 and 1897, R. B. Morin et al. disclose a method of synthetically producing a cephalosporin from a penicillin.
It is also known that Cephalosporium acremonium (C. acremonium) can synthesize both penicillin N and cephalosporin C by fermentation. In this process, the amino acids L-.alpha.-aminoadipic acid, L-valine, and L-cysteine are formed by the culture and used as precursors. The antibiotic activity of both cephalosporin C and penicillin N can be destroyed if they are treated with cephalosporinase, an enzyme which is prepared from Enterobacter cloacae. Penicillinase, a commercially available enzyme, destroys the antibiotic activity of penicillin N but has no detectable effect on the cephalosporins.
As used throughout this specification and claims, the term "cephalosporin" will thus refer to a .beta. lactam antibiotic substance which loses its antibiotic activity when exposed to cephalosporinase but is not affected by penicillinase.